Urinary incontinence is defined by the International Continence Society as the objective demonstration of involuntary loss of urine. Over 13 million American men and women suffer from urinary incontinence. Urinary incontinence causes many social and economic problems, such as loss of self-esteem, embarrassment, restriction of social and sexual activities, isolation, and dependence on caregivers. Urinary incontinence may also lead to many medical complications, for example, skin rashes, the lower urinary tract inflammation, and bladder and kidney infections.
There are five basic types of urinary incontinence based on the pattern of symptoms: (1) stress incontinence, which is involuntary loss of urine during coughing, sneezing, laughing, or other physical activity; (2) urge incontinence, which is involuntary loss of urine associated with an abrupt or strong desire to void; (3) overflow incontinence, which is involuntary loss of urine associated with over-distension of the bladder; (4) mixed incontinence, which is a combination of at least two of the above types; and (5) functional incontinence, which refers to urine loss resulting from the inability to get to a toilet. Among these types, stress incontinence and urge incontinence are two major types. The underlying pathology of stress incontinence involves the dysfunction of rhabdosphincter which is responsible for contraction of the urethral smooth muscle and of the external striated sphincter to ensure the closure of the bladder during the urine filling phase. The underlying pathology of urge incontinence involves disturbance in bladder functions as a result of unrestricted contractions of the detrusor muscle. Chutka, D. S. and Takahashi P. Y., Drugs 560: 587-595 (1998).
Urinary incontinence can have many etiologies, some are transient (transient incontinence) while others are of a more permanent nature (established incontinence). Transient incontinence is most often caused by bladder or lower urine tract infections. Established incontinence may be caused by brain and spinal cord disorders such as stroke, Alzheimer's disease, and multiple sclerosis; diseases that affect the nerves leading to and from the bladder such as diabetes; conditions in the lower urinary tract such as an enlarged prostate; and conditions that permanently impair mental function or mobility.
Under normal conditions, the lower urinary tract functions through a system of highly coordinated processes that involve the control of smooth and skeletal muscles of the bladder and urethra, by both central and peripheral nervous systems. Therefore, urinary incontinence is also regarded as a neuromuscular disorder when dysfunctional muscles of the bladder and urethra are caused by damaged nerve systems. Like most other neuromuscular disorders, such damages often arise from or are characterized by oxidative damages or stress. Recent studies reported the link between oxidative stress/increased free-radicals and urinary incontinence. Levin, R. M., et al. Oxidative Stress and Lower Urinary Tract Dysfunctions Primarily Found in Women, Urological Science, 21, 8-18 (2010); Kurutas E. B., et al. The Effects of Oxidative Stress in Urinary Tract Infection, Mediators of Inflammation, 4, 242-244 (2005).
Treatment options for urinary incontinence range from more conservative approaches, including behavioral techniques and physical therapy to more aggressive options, such as surgery. For most patients suffering minor to moderate urinary incontinence symptoms, medications, optionally in conjunction with behavioral techniques, are preferred treatment. Current medications focus on treating urinary incontinence with substances that act on the reflexes of the lower urinary tract. These medications include parasympatholytics such as oxybutynin (Ditropan), tolterodine (Detrol), darifenacin (Enablex), solifenacin (Vesicare) or trospium (Sanctura), tricyclic antidepressants such as imipramine (Tofranil), or muscle relaxants such as flavoxate. Other medications increase the tone of the urethral sphincter such as Duloxetine (Yentreve), and topical creams tone and rejuvenate tissues in the urethra and vaginal areas such as topical estrogen. However, most of them have adverse effects that greatly limit the use thereof. Burgard et al, New pharmacological treatments for urinary incontinence and overactive bladder, Curr. Opin. Investig. Drugs. 6, 81-89 (2005); Ouslander J. G. Management of Overactive Bladder, N. Engl. J. Med. 350:786-99 (2004).
There is a clear need for new, well-tolerated therapies that effectively treat urinary incontinence and achieve the greatest possible long-term improvement in patients affected by urinary incontinence, either as monotherapy or in combination with available therapies.
As set forth in more detail hereafter, the present invention is based on pharmaceutical compositions comprising at least one nitrone spin trap for the prevention and treatment of urinary incontinence and other lower urinary tract dysfunctions.
Nitrone spin traps are potent free radical scavengers and are commonly used as research aids or diagnostic tools to detect free radicals. Sudha Rana, Electron paramagnetic resonance spectroscopy in radiation research: Current status and perspectives, J. Pharmacy & BioAllied Sciences, 2, 80-87 (2010). Nitrone spin traps have strong antioxidant capabilities and have been suggested for various therapeutic uses. For example, PBN and derivatives thereof have been reported for treating a wide variety of disease conditions arising from or characterized by free radical-induced oxidative damages. Such disease conditions include, for example, disorders of the central and peripheral nervous systems, such as stroke, Parkinsonism, traumatic nerve damage and the like, and disorders of the peripheral organs, such as atherosclerosis, cardiac infarction, ulcerative colitis and the like. Nitrone spin traps have also been reported to treat certain inflammatory conditions, such as asthma and arthritis.
It would be desirable to have an effective treatment for urinary incontinence using nitrone spin traps.